Platelet mitochondrial DNA methylation: A novel biomarker for myocardial infarction - A preliminary study.

BACKGROUND: Platelet activation and thrombus formation play critical roles in the pathogenesis of myocardial infarction (MI). In addition to their role in energy production, platelet mitochondria also regulate cellular functions related to apoptosis, oxidative stress, and inflammation. Epigenetic modifications of platelet mitochondrial DNA (mtDNA) may influence platelet function and are believed to be an important factor in MI. Therefore, the aim of this study was to investigate the differences in platelet mtDNA methylation levels between MI patients and controls. METHODS: The present study utilized propensity score matching to generate 45 multivariate matched apparently healthy controls for 45 patients with newly-onset acute MI. Platelet mtDNA methylation levels were assessed through bisulfite-PCR pyrosequencing and compared between the two groups, with further adjustments made in the sensitivity analysis. RESULTS: Among the measured mitochondrial genes (MT-COX1, MT-COX2, MT-COX3, MT-ND5, MT-ATP6 and tRNA_Leu), patients with MI exhibited statistically significant differences in mtDNA methylation levels as compared to matched controls. Specifically, higher levels of mtDNA methylation were observed in MT-COX1, MT-COX3, and tRNA_Leu, while a lower level was observed in MT-ATP6 (all p < 0.0001). These results remained robust in the sensitivity analysis. CONCLUSION: Our study demonstrated significant variations in platelet mtDNA methylation levels between patients with MI and controls. Platelet mtDNA methylation may serve as a novel biomarker for MI. This observation also provided some insights into the etiology of MI.

[Nilotinib-loaded gelatin methacryloyl microneedles patch for the treatment of cardiac dysfunction after myocardial infarction].

The study aimed to evaluate the therapeutic effect of nilotinib-loaded biocompatible gelatin methacryloyl (GelMA) microneedles patch on cardiac dysfunction after myocardial infarction(MI), and provide a new clinical perspective of myocardial fibrosis therapies. The GelMA microneedles patches were attached to the epicardial surface of the infarct and peri-infarct zone in order to deliver the anti-fibrosis drug nilotinib on the 10th day after MI, when the scar had matured. Cardiac function and left ventricular remodeling were assessed by such as echocardiography, BNP (brain natriuretic peptide) and the heart weight/body weight ratio (HW/BW). Myocardial hypertrophy and fibrosis were examined by WGA (wheat germ agglutinin) staining, HE (hematoxylin-eosin staining) staining and Sirius Red staining. The results showed that the nilotinib-loaded microneedles patch could effectively attenuate fibrosis expansion in the peri-infarct zone and myocardial hypertrophy, prevent adverse ventricular remodeling and finally improve cardiac function. This treatment strategy is a beneficial attempt to correct the cardiac dysfunction after myocardial infarction, which is expected to become a new strategy to correct the cardiac dysfunction after MI. This is of great clinical significance for improving the long-term prognosis of MI patients.

Galunisertib-Loaded Gelatin Methacryloyl Hydrogel Microneedle Patch for Cardiac Repair after Myocardial Infarction.

Uncontrolled and excessive fibrosis after myocardial infarction (MI) in the peri-infarct zone leads to left ventricular remodeling and deterioration of cardiac function. Inhibiting fibroblast activation during the mature phase of cardiac repair improves cardiac remodeling and function after MI. Here, we engineered a biocompatible microneedle (MN) patch using gelatin methacryloyl and loaded it with galunisertib, a transforming growth factor-beta (TGF-ß)-specific inhibitor, to treat excessive cardiac fibrosis after MI. The MN patch could sustainably release galunisertib for more than 2 weeks and provide mechanical support for the fragile ventricular wall. After being applied to a rat model of MI, the galunisertib-loaded MN patch improved long-term cardiac function and reduced cardiac fibrosis by effectively inhibiting TGF-ß depending on fibroblast activation. This strategy shows the potential of the MN patch as an advanced platform to locally deliver direct antifibrotic drugs to prevent myocardial fibrosis for the treatment of MI and the promotion of cardiac repair.

Trimethylamine N-Oxide Promotes Abdominal Aortic Aneurysm Formation by Aggravating Aortic Smooth Muscle Cell Senescence in Mice.

Trimethylamine N-oxide (TMAO) has been linked to cardiovascular disease morbidity and mortality. However, the role of TMAO in the development of abdominal aortic aneurysms (AAAs) is not known. This study investigated the association between TMAO and AAA formation. TMAO and saline were added to the drinking water of angiotensin II (AngII)- and calcium chloride (CaCl2)-induced AAA model mice, respectively. After 4 weeks, the effects of TMAO on AAA development were determined by histology and immunohistology of aortic tissue. The in vitro effects of TMAO were also examined in mouse aortic smooth muscle cells (SMCs). The maximal aortic diameter, incidence of AAA, and degree of elastin degradation were significantly increased in TMAO-treated mice. TMAO also increased the accumulation of the senescence markers p21 and p16, as well as of reactive oxygen species (ROS), matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9) in vivo and in vitro. TMAO promoted AAA development in mouse AAA models induced by AngII and CaCl2 by a mechanism involving cellular senescence.